Leishmania is transmitted to its mammalian host by the bite of phlebotomine sand flies. Within the mammalian host, Leishmania is an obligate intracellular parasite of macrophages. Immunity to leishmaniasis appears to be due to the elaboration of macrophage activating factors by parasite specific T cells which allow the macrophage to destroy its parasite burden. It is, however, surprising that this specific immunity is required since Leishmania can be readily destroyed by host non-specific immune forces (e.g., complement) and, within the macrophage, the parasite must somehow survive in the hostile environment of the phagolysosome. A partial answer to this enigma has been supplied by the work of Sacks and colleagues who described metacyclic forms of Leishmania which develop in the sand fly and are more resistant to degradation by complement and macrophages. However, the metacyclic parasites were still not completely resistant to either of these host defense mechanisms. Therefore, the parasite is likely to have other means by which it evades these initial non-specific host defense mechanisms as well as the later onslaught of specific T cell immunity. When the sand fly bites the mammalian host, it salivates into the skin. The saliva of the fly contains a number of potent pharmacological activities and it has recently been shown in the applicant's laboratory that sand fly saliva dramatically enhances Leishmania infectivity for mice and blocks macrophage activation. It therefore becomes important to examine the effect of saliva from various species of sand flies on Leishmania and on macrophage functions. These studies will be performed on both a biochemical and molecular level and could result in the description of novel forms of immunoregulation. The experiments will also attempt to characterize and isolate the various activities found in sand fly saliva in order to determine the mode of action of each substance. Finally, it is possible that in nature sand fly saliva is critical to the initiation of infection with Leishmania in the mammalian host, and, if its activity were neutralized, infection would be prevented. Therefore, animals will be immunized with saliva, or the relevant components thereof, in an attempt to vaccinate against leishmaniasis.